The number of patients affected by Alzheimer's disease (AD) or by diabetes is increasing with the aging of the population and the type 2 diabetes "epidemic". There is growing evidence of links between AD and diabetes, with AD patients showing impaired insulin function while cognitive deficits and increased risk of developing AD occur in both type 1 and type 2 diabetic patients. The reasons for the increased risk are not known, but both diseases have a neurodegenerative etiology and may share common mechanisms that culminate in neurodegeneration. Our recent studies of the insulin-signaling pathway have revealed new potential links between AD and diabetes with a particular interest in glycogen synthase kinase 3 (GSK3), an enzyme that both modulates amyloid 2 formation, and also phosphorylates tau, facilitating neurofibrillary tangle formation, the 2 major hallmarks of AD. With this project, we propose to understand the role of defective insulin-signaling pathway in the common pathogenic events leading to AD. The use of both type of diabetes (type 1: insulin-deficient diabetes and type 2: insulin-resistant diabetes) and a number of transgenic mice models will answer the question if diabetes hastens the onset and progression of AD via disturbance of the insulin-signaling pathway. This proposal aims at understanding if defects of the insulin-signaling leads to disturbance of the cytoskeleton (tau) and consequently disrupted axonal transport, therefore disrupted neurotrophic support using neurons in culture in diabetic conditions or hippocampal neurons isolated from the different mice models combining AD and diabetes we propose to use. To follow on our hypothesis of disrupted support to hippocampal neurons, we propose to establish in vivo efficacy of neurotrophic peptides. We anticipate that the studies we propose will bring new understanding on the mechanisms leading to enhanced progression of AD due to diabetes and will extend the limited choice of therapy that is currently available for the treatment of AD. PUBLIC HEALTH RELEVANCE: Assorted epidemiologic and animal studies suggest a link between Alzheimer's disease and diabetes. It is likely to become a growing issue as the life expectancy of the type-1 diabetic population increases along with the increasing number of newly diagnosed patients with type 2 diabetes. The study of the neurodegenerative link between the 2 diseases we propose aims at understanding the mechanisms leading to Alzheimer's disease and to extend the limited choice of therapy that is currently available for its treatment.